Cutaneous malignant melanoma is the leading cause of skin cancer-related deaths. Its incidence has increased worldwide faster than any other cancer, with 5-year survival rates for patients with distant metastatic disease being less than 20% (see the world wide web at seer.cancer.gov/csr/1975_2007). Improvement of clinical outcomes for this aggressive, chemo- and radio-resistant, disease remains a major clinical challenge. Significant progress in our understanding of the etiologies and genetic underpinnings of melanoma has nevertheless been made.1, 2 These advances have recently led to promising results in trials of targeted therapies for this disease.3 The Ras/Raf/MEK/ERK pathway has been identified as the main regulator of cell proliferation in melanoma, with ERK being hyperactivated in up to 90% of human melanomas.4 Activating NRAS mutations are a common route to activating this pathway; mutations affecting codon 61 being the most prevalent (NRASQ61K).5, 6 
BRAF, one of the three human RAF genes, is also frequently mutated in melanomas,7 with the most common mutation being a glutamic acid for valine substitution at position 600 (V600E).7 BRAFV600E stimulates constitutive ERK signaling, leading to melanocyte hyper-proliferation.8 Early clinical experience with the novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumor response rate among patients with BRAFV600E-positive melanomas; unfortunately, patients acquire drug resistance within a few months of an initial response.9 Because of its ability to acquire drug resistance, its chemoresistance and because melanoma is a highly dynamic and genetically heterogeneous tumor, novel treatment strategies and combination therapies are urgently needed. Restoration of the wild-type p53 tumor suppressor function has emerged as an attractive anti-cancer strategy for many tumor types.10-12 
Whether this approach can be therapeutically beneficial in malignant melanoma remains unknown. p53 pathway inactivation, which mainly arises as a consequence of inactivating mutations or allelic loss of the p53 gene itself, is the most common molecular defect in human cancers.13 Intriguingly, the p53 locus is intact in over 95% of melanoma cases,14 raising questions as to the pathogenic relevance of p53 in the etiology of melanoma tumor formation. At the same time, there is an increasing body of evidence supporting a relevant role for p53 in melanoma development. Loss of p53 cooperates with melanocyte-specific overexpression of activated HRASV12G and BRAFV600E in promoting melanomagenesis in mice15, 16 and oncogenic NRAS cooperates with p53 loss to generate melanomas in zebrafish.17 
Cancers that retain expression of wild-type p53 often find alternative ways to subvert p53 function, through either deregulation of upstream modulators and/or inactivation of downstream effectors.18 MDM2, which encodes an E3 ubiquitin ligase that control p53 levels and function,19 is amplified in human melanomas but only in 3%-5% of documented cases.20 The INK4A-ARF (CDKN2A) locus is often deleted or inactivated in heritable and sporadic melanoma.1 This locus encodes two distinct tumor suppressors, p16INK4A (referred hereafter as INK4A) and p14ARF (referred hereafter as ARF). INK4A positively regulates the pRB tumor suppressor and ARF is a potent MDM2 antagonist. Thus, decreased ARF expression or its complete loss could, in part, compromise p53 function in melanoma.21 However, p53-independent functions of ARF have been described22 and whether ARF restricts melanoma progression in a p53-dependent manner is still a matter of debate.23 Overall, although several oncogenic events that compromise p53 function have been described in melanoma the number and the frequency of these events accounts for only a small proportion of melanoma cases, implying that additional, unidentified, mechanisms exist. Unveiling such mechanisms may lead to the development of novel targeted therapeutic strategies allowing re-activation of p53 tumor killing activities.